Process for concentrating aqueous solutions of camphorsulfonic acid



United States Patent 3 221,046 PROCESS FOR CQNCENTRATING AQUEOUSSULUTIQNS 6F CAMPHURSULFGNIC ACED David A. Johnson, Fayetteville, andGlenn A. Hardcastle,

31:, Syracuse, N.Y., assignors to Bristol-Myers Company, New York, N.Y.,a corporation of Delaware No Drawing. Filed Apr. 2, 1963, Ser. No.26?,868

3 Claims. (Cl. 260503) This application relates to a novel and highlyuseful process for the recovery of d-IO-camphorsulfonic acid and, moreparticularly, to a highly efficient process for the purification andconcentration of aqueous solutions of d-l0-camphorsulfonic acid.

Resolutions of racemic bases are carried out by means of the use ofd-IO-camphorsulfonic acid but it is a costly reagent and it must berecovered efiiciently for re-use to avoid prohibitive expense. Theefficient recovery of this acid is rendered difiiculty by its extremesolubility in water. Its recovery, as by absorption on and elution from,an ion exchange resin, provides recovered acid in the form of diluteaqueous solutions which must be concentrated, as by vacuum distillation,at considerable cost. In addition it is found that ammonium ioninterferes with resolutions and must therefore be removed from recoveredacid.

An example of such a resolution involves the therapeutic agenta-aminobenzylpenicillin which occurs as tWo diastereoisomers. Thecommercial form, named D-(-), is the isomer prepared by condensation ofnatural 6- aminopenicillanic acid and D-()-2-phenylglycine having aspecific rotation in 1 N HCl of about -l57. For the synthesis of thisproduct it is therefore necessary to resolve the synthetic, andtherefore racernic, 2-pl1enylglycine which is the available startingmaterial.

It is the object of the present invention to provide a highly efiicientand inexpensive method for purifying and concentrating impure,relatively dilute aqueous solutions of d-l0-camphorsulfonic acid, e.g.the liquors remaining after resolution of 2-phenylglycine with saidacid.

The object of the present invention has been attained by the provision,according to the present invention, of a process of preparing apurified, concentrated aqueous solution of d-l0camphorsulfonic acid froman impure, relatively dilute aqueous solution thereof which comprisesthe consecutive steps of (a) mixing at about pH 3-6 and impure diluteaqueous solution of d-10-camphorsulfonic acid with a water-immiscible,neutral organic solvent and about one to six moles (per mole of thed-l0camphorsulfonic acid) of a member selected from the group consistingof secondary amines of the formula wherein R is an aliphatic grouphaving from 10 to 14 carbon atoms and R R and R are each alkyl groupshaving a total of 11 to 14 carbon atoms, said secondary amines beingliquid at room temperature and soluble in said organic solvent, andmixtures thereof; (b) separating from said mixture the organic solventphase; (0) mixing said organic solvent phase with a lesser volume ofwater .at a highly alkaline pH to transfer the d-lO-camphorsulfonic acidinto 'a'second aqueous phase; and (d) separating and then acidifyingsaid second aqueous phase to provide a purified, concentrated aqueoussolution of d-10-camphorsu1fonic acid.

A preferred and highly specific embodiment of the present inventioncomprises the process of preparing a purified, concentrated aqueoussolution of d-IO-Camphorsulfonic acid from an impure, relatively diluteaqueous solution thereof which comprises the consecutive steps of (a)mixing at about pH 4-5 an impure, dilute aqueous solution ofd-lO-camphorsulfonic acid with about two volumes of toluene as awater-immiscible, neutral organic solvent and about two or six moles(per mole of the d-10- campshorsulfonic acid) of a member selected fromthe group consisting of secondary amines of the formula wherein each ofR R and R is an aliphatic hydrocarbon radical and R R and R contain inthe aggregate from 11 to 14 carbon atoms, said secondary amines beingliquid at room temperature and soluble in said organic solvent, andmixtures thereof; (b) separating from said mixture the organic solventphase; (c) mixing said organic solvent phase with a lesser volume ofwater at a pH above 9.0 to transfer the d-lO-camphorsulfonic acid into asecond aqueous phase; and (d) separating and then acidifying said secondaqueous phase to provide a purified, concentrated aqueous solution ofd-lO-camphorsulfonic acid.

The starting materials for the operation of the process of the presentinvention can be, for example, separate aqueous solutions of thed-lO-camphorsulfonic acid salts of L-(+)-2-phenylglycine andD-()-2-phenylglycine. The addition to a solution of either salt ofconcentrated ammonium hydroxide (as to pH 7-8) or of a strong base suchas 50% NaOH (as to pH 4.5) causes the precipitation in its amphotericform of the appropriate isomer of Z-phenylglycine and leaves afterfiltration an aqueous solution of the corresponding ammonium or metalsalt of dl0-camphorsulfonic acid.

These solutions, which may be combined, are then adjusted to about pH3-6, and preferably about pH 4.0- 5.0, and mixed thoroughly with asolution in about one to ten volumes, and preferably about two volumes,of a water-immiscible, neutral organic solvent such as butanol, methylisobutyl ketone or, preferably, toluene (or a similar solvent having anegligible solubility in water) of at least one mole, and preferablyabout 2-6 moles (per mole of salt), of the amines and mixtures thereofwhich are liquid at room temperatures and soluble in the organic solventand which have the formula H R R1 I( JR wherein R is an aliphatic grouphaving from 10 to 14 carbon atoms and R R and R are each alkyl groupshaving in the aggregate a total of from 11 to 14 carbon atoms.

A preferred group of amines of the class described above are thoseamines and mixtures thereof which have the formula wherein each of R Rand R is an aliphatic hydrocarbon radical and wherein R R and R containin the aggregate from 11 to 14 carbon atoms; this particular mixture ofsecondary amines, which is sometimes referred to as Liquid Amine MixtureNo. I, is a clear amber liquid having the following physicalcharacteristics: viscosity at 25 C. of 70 cps; specific gravity at 20 C.of 0.845; refractive index at 25 C. of 1.467; distillation range at 10mm.: up to C.4%, 160 to 210 C.5%, 210 to 220 C.74%, above 220 C.-

17%. Another preferred group of amines of the class described above is amixture of secondary amines wherein each secondary amine has the formulat t CI'I;i(ClElI-i)1 CHzN-(l3--R wherein each of R R and R is amonovalent aliphatic hydrocarbon radical and wherein R R and R containin the aggregate from 11 to 14 carbon atoms. This particular mixture ofsecondary amines, which is sometimes referred to as Liquid Amine MixtureNo. II, is a clear amber liquid having the following physicalcharacteristics: viscosity at 25 C. of 70 cps., specific gravity at 20C. of 0.826; refractive index at 25 C. of 1.4554; distillation range at10 mm., up to 170 C.-0.5%, 170 to 220 C.-3%, 220 to 230 C.90% and above230 C.6.5%. Liquid Amine Mixture No. I and Liquid Amine Mixture No. IIare available from Rohm and Haas Company, Washington Square,Philadelphia 5, Pa., as Amber-lite LA-l and mberli-te LA-2,respectively.

Upon separation the solvent-amine solution contains thed-lO-camphorsulfonic acid, which is extracted therefrom into water (e.g.about one-sixth volume) by adjusting the pH to a highly alkaline point(ire. to at least pH 9.0, as to pH 9.1 with 50% NaOH). Only enough baseneed be used to convert the amine to the base form; this is indicated bya sharp pH change at about pH 8-9. The water layer containing thed-lO-camphorsulfonic acid is separated and the solvent-amine phase isre-extracted if desired and the aqueous extracts combined. Addition ofconcentrated acid, e.g. conc. HCl in the minimum amount necessary toconvert all of the d-lO-camphorsulfonic acid salt to the acid form, thengives an aqueous solution containing 95% of the originald-lO-camphorsulfonic acid which is completely suitable for theresolution of fresh Z-phenylglycine. This solution is so used byaddition thereto of about one mole of Z-phenylglycine per 1.3 moles ofthe d-lO-camphorsulfonic acid with stirring at an elevated temperature,e.g. 60-70 C., to form a slurry which dissolves on further heating, e.g.to about 85-90 C., is decolorized by charcoal if desired, filtered hotand then cooled slowly to precipitate selectively the desiredd-lO-camphorsulfonic acid salt of D-(-)-2- phenylglycine in high yield.Filtration then gives as the filtrate an aqueous solution of excessd-lO-camphorsulfonic acid and the d-lO-camphorsulfonic acid salt ofL-(+)-2- phenylgylcine. The solid d-lO-camphorsulfonic acid salt ofD-(-)-2-phenylglycine dissolves in about three times its weight of waterat about 85-90 C., thus completing the cycle as described above.

In addition, the recovered but undesired L-(+)-2- phenylgylcine iseasily racemized by refluxing for an extended period of time, e.g. eighthours, in water containing -20% by weight of caustic, e.g. sodiumhydroxide. Upon cooling and adjusting to about pH 7, there isprecipitated racemic 2-phenylglycine of good quality and high yieldwhich is suitable for recycling. The process of the present invention isequally applicable to the recovery of d--camphorsulfonic acid frommother liquors obtained in the resolution of other amines andparticularly of a-amino-acids including substituted Z-phenylglycinessuch as those disclosed in U.S. Patent 2,985,648.

The following example will serve to illustrate the present inventionwithout limiting it thereto.

EXAMPLE (A) The isolation of D-()-2-phenylglycine Step 1.-To 100 g.(0.43 mole) of d-IO-camphorsulfonic acid (CSA) in 300 ml. water at 60-70C. there is added 50 g. (0.33 mole) of racemic 2-phenylglycine (P6) withstirring to form a slurry of the CSA salts of 4 L-(+)-2-phenylglycineand D-()-2-phenylglycine, hereinafter called CSA-L(+)PG and GSA-D()PG.

Step 2.The slurry is heated until it dissolves at approximately -90 C.and there is then added 3.74 g. of activated charcoal (Darco KB Step3.The solution containing charcoal is stirred for 10-15 minutes atapproximately C. and filtered hot to remove the charcoal, which iswashed with 50 ml. hot water.

Step 4.--The filtrate is stirred and cooled very slowly to about 15 C.over four hours. It is then cooled to 5 C. and held there for three orfour hours, precipictating GSA-D()PG.

Step 5 .The solid GSA-D()PG is collected by filtration and washed with50 ml. ice-cold water. The filtrate (mother liquor) containingCSA-L(+)PG and excess CSA is saved for recovery of the CSA andracemization of the L(+)PG.

Step 6 .-The yield of wet, solid GSA-D()PG is about 62 g. (90% solids).

Step 7.The CSA'D()PG cake from Step 5 is mixed while still damp withthree times its weight of water, stirred and heated at about 85-90 C.until it dissolves.

Step 8.The hot solution is filtered through diatomaceous earth(Dicalite) which is then washed with 25 ml. hot water.

Step 9.-To the hot filtrate while stirring there is added sufificientconcentrated ammonium hydroxide (about 16 ml.) to adjust the pH to therange of 7-8. The D(-) PG precipitates in crystalline form.

Step 10.The crystalline slurry is stirred and cooled to 0-5 C. over atwo-hour period while maintaining the pH at 7-8, filtered and the D()PGcake is washed with 25 ml. ice-cold water.

Step 11.The collected D()PG is dried in an oven at 50-60 C. and found toweigh about 19 g. (76% of theory) and to have a specific rotation ofabout Step 12.The filtrate (mother liquor) from Step 10 is reserved forrecovery of CSA.

(B) The isolation and racemization of L-(-|-)-2- phenylglycine Step13.The mother liquor from Step 5 containing CSA-L(+)PG and excess CSA isadjusted to pH 4.5 with 50% NaOH solution with stirring and theresulting slurry of crystalline L(+)PG is cooled to 0-5 C., col-lectedby filtration and washed with 75 ml. cold water.

The filtrate (mother liquor) is saved for recovery of the CSA therein.

The solid L(+)PG is slurried in about 475 ml. water or, preferably, inthe extracted water from Step 14 below, and, after adding a number ofgrams of solid caustic equal to 10% of the volume of water in ml., thesolution is refluxed for eight hours. The mixture is then cooled to -10C., adjusted to pH 7 with HCl and stirred two hours. The precipitatedracemic 2-phenylglycine is collected by filtration, washed with coldwater, dried and is then ready for re-use.

(C) The recovery of CSA Step 14.-The CSA-containing mother liquor fromStep 13 is mixed with a solution of 400 ml. (0.9 mole) of Liquid AmineMixture No. I in 800 ml. toluene and the pH is adjusted to 45-50 withcone. HCl or 50% NaOH. After thorough mixing the two layers areseparated. The toluene phase contains the CSA. The aqueous phase is setaside for use in Step 13.

Step 15.-The CSA-containing toluene phase from Step 14 is mixed with theCSA-rich mother liquor of Step 12 and the pH is adjusted to 4.5-5.0.After thorough mixing and separating, there is obtained a toluene phasecontaining virtually all of the CSA used originally in Step 1.

Step 16.To the GSA-containing toluene phase of Step 15 there is added200 ml. water and the pH of the mixture O is adjusted to 9.1 with 50%NaOH (about 38 ml.) while mixing thoroughly. Upon separation there isobtained an aqueous phase containing the CSA and a toluene phase.

Step 17.The toluene phase from Step 16 is re-extracted with 50 ml. waterand the aqueous extract is combined with that from Step 16. To thecombined CSA- containing aqueous extracts there is then added 34.2 ml.(0.41 mole) concentrated HCl and 5.0 g. fresh CSA. This solution is thenfiltered through diatomaceous earth (Dicalite) to clarify it. The filtercake is washed with enough water to bring the volume of filtrate up to400 ml. The filtrate thus obtained contains 100 g. CSA and is fullysuitable for use in another cycle, i.e. by adding thereto at 60-70" C.50 g. racemic 2-phenylglycine as in Step 1 and proceeding as before.

While various embodiments have been described in some detail it will beunderstood that modifications can be made in the procedures describedwithout departing from the scope of the invention. Certain agents,compounds, or mixtures (e.g. acids, bases, solvents and the like) andother details described or equivalent to those described in relation toone procedure may be employed in connection with other procedures. Forexample, in the event that the impure, dilute aqueous solution ofd-lO-camphorsulfonic acid is quite dilute, i.e. about 1%, it is nolonger necessary or even advisable to use an equal volume of thewater-immiscible neutral organic solvent and in such case the volume ofsaid solvent need be only one-tenth the volume of the aqueous solutionor even less as determined by simple test.

We claim:

1. The process of preparing a purified, concentrated aqueous solution ofd-lO-camphorsulfonic acid from an impure, relatively dilute aqueoussolution thereof which comprises the consecutive steps of (a) mixing atabout pH 3-6 an impure, dilute aqueous solution of d-lO-camphorsulfonicacid with a waterimmiscible, neutral organic solvent and about one tosix moles (per mole of the d--camphorsulfonic acid) of at least onesecondary amine of the formula wherein each of R R and R is an aliphatichydrocarbon radical and R R and R contain in the aggregate from 11 to 14carbon atoms, said secondary amines being liquid at room temperature andsoluble in said organic solvent;

(b) separating from said mixture the organic solvent phase;

(c) mixing said organic solvent phase with a lesser volume of Water at apH above 9.0 to transfer the d-lO-camphorsulfonic acid into a secondaqueous phase; and

(d) separating and then acidifying said second aqueous phase to providea purified, concentrated aqueous solution of d-IO-camphorsulfonic acid.

2. The process of preparing a purified, concentrated aqueous solution ofd-lO-camphorsulfonic acid from an impure, relatively dilute aqueoussolution thereof which comprises the consecutive steps of (a) mixing atabout pH 45 an impure, dilute aqueous solution of d-lO-camphorsulfonicacid with about two volumes of a water-immiscible, neutral organicsolvent and about two to six moles (per mole of the 6d-lO-camphorsulfonic acid) of at least one secondary amine of theformula wherein each of R R and R is an aliphatic hydro carbon radicaland R R and R contain in the aggregate from 11 to 14 carbon atoms, saidsecondary amines being liquid at room temperature and soluble in saidorganic solvent;

(b) separating from said mixture the organic solvent phase;

(c) mixing said organic solvent phase with a lesser volume of water at apH above 9.0 to transfer the d-lO-camphorsulfonic acid into a secondaqueous phase; and

(d) separating and then acidifying said second aqueous phase to providea purified, concentrated aqueous solution of d-IO-camphorsulfonic acid.

3. The process of preparing a purified, concentrated aqueous solution ofd-10-camphorsulfonic acid from an impure, relatively dilute aqueoussolution thereof which comprises the consecutive steps of (a) mixing atabout pH 36 an impure, dilute aqueous solution of d-10-camphorsulfonicacid with toluene as a water-immiscible, neutral organic solvent andabout one to six moles (per mole of the d-lO-camphorsulfonic acid) of atleast one secondary amine of the formula References Cited by theExaminer FOREIGN PATENTS 8/1953 France. 2/1937 Hungary.

OTHER REFERENCES Houben-Weyl: Methoden der Organischen Chemie, vol. 4,part II, 1955, pp. 513-523.

References Cited by the Applicant UNITED STATES PATENTS 2,985,648 5/1961Doyle et al. 3,008,956 11/1961 Nettleton et a1.

LORRAINE A. WEINBERGER, Primary Examiner. LEON ZITVER, Examiner.

1. THE PROCESS OF PREPARING A PURIFIED, CONCENTRATED AQUEOUS SOLUTION OFD-10-CAMPHORSULFONIC ACID FROM AN IMPURE, RELATIVELY DILUTE AQUEOUSSOLUTION THEREOF WHICH COMPRISES THE CONSECUTIVE STEPS OF (A) MIXING ATABOUT PH 3-6 AN IMPURE, DILUTE AQUEOUS SOLUTION OF D-10-CAMPHORSULFONICACID WITH A WATERIMMISICIBLE, NEUTRAL ORGANIC SOLVENT AND ABOUT ONE TOSIX MOLES (PER MOLE OF THE D-10-CAMPHORSULFONIC ACID) OF AT LEAST ONESECONDARY AMMINE OF THE FORMULA